Estrogens protect against heart disease. This protection has been attributed to estrogen-mediated beneficial changes in plasma lipoprotein levels. Recent data has clearly shown estrogen-mediated inhibition of atherogenesis in the absence of lipoprotein changes, suggesting other important mechanisms of estrogen protection. I hypothesize that estrogens inhibit atherogenesis in part by selectively protecting high density lipoprotein (HDL) from deleterious oxidation. Oxidation of HDL is known to compromise its role in reverse cholesterol transport, thereby reducing its protective effects. Oxidation is predicted to render HDL less able to protect low density lipoprotein (LDL) from oxidation and to increase the catabolic rate for HDL. The prospect that estrogens protect HDL from damage that compromises its functions or accelerates its clearance adds a new dimension to our understanding of HDL protection in women. This proposal will test the following hypothesis: 1) a direct relationship exists between estrogen-mediated antioxidant protection of HDL and decreased atherogenesis in vivo; 2) antioxidant effects and hormonal effects of estradiol can be dissociated by structural alteration of the steroid; 3) estrogens selectively protect HDL from oxidation; and 4) selective estrogen protection of HDL results from HDL-mediated esterification of estrogens. Comparison of the structure/antioxidant activity relationship for a panel of estrogens will identify the most effective naturally occurring estrogenic antioxidants for HDL. In addition, it will establish the key structural requirements of a potent antioxidant. This could lead to the design of a steroid antioxidant that does not bind receptor and, therefore, has no feminizing activity. Such a drug will be suitable for use in men. The potential for an antioxidant that could be administered by transdermal patch is evident. In addition, I will define the most potent antioxidant of the receptor-active estrogens, information useful for estrogen replacement therapy in postmenopausal women. Elucidating the mechanism of the selective estrogen protection of HDL will add to our understanding of this complex lipoprotein. The information gained through testing these hypotheses will enhance our knowledge of the atheroprotective effects of estrogen.